Genetic Insights for Drug Development in NAFLD

被引：59

作者：

Eslam, Mohammed ^{[1
,2
]}

George, Jacob ^{[1
,2
]}

机构：

[1] Westmead Hosp, Westmead Inst Med Res, Storr Liver Ctr, Westmead, NSW, Australia

[2] Univ Sydney, Westmead, NSW, Australia

来源：

TRENDS IN PHARMACOLOGICAL SCIENCES | 2019年 / 40卷 / 07期

基金：

英国医学研究理事会;

关键词：

NONALCOHOLIC FATTY LIVER; GENOME-WIDE ASSOCIATION; RS641738 INCREASES RISK; ISCHEMIC-HEART-DISEASE; MENDELIAN RANDOMIZATION; CONFERS SUSCEPTIBILITY; CARDIOVASCULAR-DISEASE; AMERICAN ASSOCIATION; HEPATIC STEATOSIS; VARIANT;

D O I：

10.1016/j.tips.2019.05.002

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Drug development is a costly, time-consuming, and challenging endeavour, with only a few agents reaching the threshold of approval for clinical use. Therefore, approaches to more efficiently identify targets that are likely to translate to clinical benefit are required. Interrogation of the human genome in large patient cohorts has rapidly advanced our knowledge of the genetic architecture and underlying mechanisms of many diseases, including nonalcoholic fatty liver disease (NAFLD). There are no approved pharmacotherapies for NAFLD currently. Genetic insights provide a powerful and new approach to infer and prioritise candidate drugs, with such selection avoiding myriad pitfalls, while defining likely benefits. In this review, we discuss the prospects and challenges for the optimal utilisation of genetic findings for improving and accelerating the NAFLD drug discovery pipeline.

引用

页码：506 / 516

页数：11

共 106 条

[1] Mutations in PCSK9 cause autosomal dominant hypercholesterolemia [J].

Abifadel, M ;

Varret, M ;

Rabès, JP ;

Allard, D ;

Ouguerram, K ;

Devillers, M ;

Cruaud, C ;

Benjannet, S ;

Wickham, L ;

Erlich, D ;

Derré, A ;

Villéger, L ;

Farnier, M ;

Beucler, I ;

Bruckert, E ;

Chambaz, J ;

Chanu, B ;

Lecerf, JM ;

Luc, G ;

Moulin, P ;

Weissenbach, J ;

Prat, A ;

Krempf, M ;

Junien, C ;

Seidah, NG ;

Boileau, C .

NATURE GENETICS, 2003, 34 (02) :154-156

[2] A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease [J].

Abul-Husn, N. S. ;

Cheng, X. ;

Li, A. H. ;

Xin, Y. ;

Schurmann, C. ;

Stevis, P. ;

Liu, Y. ;

Kozlitina, J. ;

Stender, S. ;

Wood, G. C. ;

Stepanchick, A. N. ;

Still, M. D. ;

McCarthy, S. ;

O'Dushlaine, C. ;

Packer, J. S. ;

Balasubramanian, S. ;

Gosalia, N. ;

Esopi, D. ;

Kim, S. Y. ;

Mukherjee, S. ;

Lopez, A. E. ;

Fuller, E. D. ;

Penn, J. ;

Chu, X. ;

Luo, J. Z. ;

Mirshahi, U. L. ;

Carey, D. J. ;

Still, C. D. ;

Feldman, M. D. ;

Small, A. ;

Damrauer, S. M. ;

Rader, D. J. ;

Zambrowicz, B. ;

Olson, W. ;

Murphy, A. J. ;

Borecki, I. B. ;

Shuldiner, A. R. ;

Reid, J. G. ;

Overton, J. D. ;

Yancopoulos, G. D. ;

Hobbs, H. H. ;

Cohen, J. C. ;

Gottesman, O. ;

Teslovich, T. M. ;

Baras, A. ;

Mirshahi, T. ;

Gromada, J. ;

Dewey, F. E. .

NEW ENGLAND JOURNAL OF MEDICINE, 2018, 378 (12) :1096-1106

[3] Hydroxysteroid (17β) dehydrogenase 13 deficiency triggers hepatic steatosis and inflammation in mice [J].

Adam, Marion ;

Heikelae, Hanna ;

Sobolewski, Cyril ;

Portius, Dorothea ;

Maki-Jouppila, Jenni ;

Mehmood, Arfa ;

Adhikari, Prem ;

Esposito, Irene ;

Elo, Laura L. ;

Zhang, Fu-Ping ;

Ruohonen, Suvi T. ;

Strauss, Leena ;

Foti, Michelangelo ;

Poutanen, Matti .

FASEB JOURNAL, 2018, 32 (06) :3434-3447

[4] The natural history of nonalcoholic fatty liver disease: A population-based cohort study [J].

Adams, LA ;

Lymp, JF ;

St Sauver, J ;

Sanderson, SO ;

Lindor, KD ;

Feldstein, A ;

Angulo, P .

GASTROENTEROLOGY, 2005, 129 (01) :113-121

[5] Genomics of Adverse Drug Reactions [J].

Alfirevic, Ana ;

Pirmohamed, Munir .

TRENDS IN PHARMACOLOGICAL SCIENCES, 2017, 38 (01) :100-109

[6] The NAFLD fibrosis score: A noninvasive system that identifies liver fibrosis in patients with NAFLD [J].

Angulo, Paul ;

Hui, Jason M. ;

Marchesini, Giulio ;

Bugianesi, Ellisabetta ;

George, Jacob ;

Farrell, Geoffrey C. ;

Enders, Felicity ;

Saksena, Sushma ;

Burt, Alastair D. ;

Bida, John P. ;

Lindor, Keith ;

Sanderson, Schuyler O. ;

Lenzi, Marco ;

Adams, Leon A. ;

Kench, James ;

Therneau, Terry M. ;

Day, Christopher P. .

HEPATOLOGY, 2007, 45 (04) :846-854

[7] Phase II and Phase III attrition rates 2011-2012 [J].

Arrowsmith, John ;

Miller, Philip .

NATURE REVIEWS DRUG DISCOVERY, 2013, 12 (08) :568-568

[8] The PNPLA3 Variant Associated With Fatty Liver Disease (I148M) Accumulates on Lipid Droplets by Evading Ubiquitylation [J].

BasuRay, Soumik ;

Smagris, Eriks ;

Cohen, Jonathan C. ;

Hobbs, Helen H. .

HEPATOLOGY, 2017, 66 (04) :1111-1124

[9] Adiponutrin, a transmembrane protein corresponding to a novel dietary- and obesity-linked mRNA specifically expressed in the adipose lineage [J].

Baulande, S ;

Lasnier, F ;

Lucas, M ;

Pairault, J .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (36) :33336-33344

[10] The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver [J].

Beer, Nicola L. ;

Tribble, Nicholas D. ;

McCulloch, Laura J. ;

Roos, Charlotta ;

Johnson, Paul R. V. ;

Orho-Melander, Marju ;

Gloyn, Anna L. .

HUMAN MOLECULAR GENETICS, 2009, 18 (21) :4081-4088

← 1 2 3 4 5 6 7 8 9 10 →